ABHD16A deficiency causes a complicated form of hereditary spastic paraplegia associated with intellectual disability and cerebral anomalies

Gabrielle Lemire; Yoko A Ito; Aren E Marshall; Nicolas Chrestian; Valentina Stanley; Lauren Brady; Mark Tarnopolsky; Cynthia J Curry; Taila Hartley; Wendy Mears; Alexa Derksen; Nadie Rioux; Nataly Laflamme; Harrol T Hutchison; Lynn S Pais; Maha S Zaki; Tipu Sultan; Adrie D Dane; Care4Rare Canada Consortium; Joseph G Gleeson; Frédéric M Vaz; Kristin D Kernohan; Geneviève Bernard; Kym M Boycott

doi:10.1016/j.ajhg.2021.09.005

ABHD16A deficiency causes a complicated form of hereditary spastic paraplegia associated with intellectual disability and cerebral anomalies

Am J Hum Genet. 2021 Oct 7;108(10):2017-2023. doi: 10.1016/j.ajhg.2021.09.005. Epub 2021 Sep 28.

Authors

Gabrielle Lemire¹, Yoko A Ito², Aren E Marshall², Nicolas Chrestian³, Valentina Stanley⁴, Lauren Brady⁵, Mark Tarnopolsky⁵, Cynthia J Curry⁶, Taila Hartley², Wendy Mears², Alexa Derksen⁷, Nadie Rioux⁸, Nataly Laflamme⁸, Harrol T Hutchison⁹, Lynn S Pais¹⁰, Maha S Zaki¹¹, Tipu Sultan¹², Adrie D Dane¹³; Care4Rare Canada Consortium; Joseph G Gleeson⁴, Frédéric M Vaz¹⁴, Kristin D Kernohan¹⁵, Geneviève Bernard¹⁶, Kym M Boycott¹⁷

Affiliations

¹ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: glemire@cheo.on.ca.
² Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
³ Department of Paediatric Neurology, Paediatric Neuromuscular Disorder, Centre Mère Enfant Soleil, Laval University, Quebec City, QC G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Neuroscience Laboratory, CHU de Québec Research Center, Laval University, Quebec City, QC G1V 4G2, Canada.
⁴ Laboratory for Pediatric Brain Disease, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA.
⁵ Neuromuscular and Neurometabolics Division, Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5, Canada.
⁶ Genetic Medicine Division, Department of Pediatrics, University of California, San Francisco, Fresno, CA 93701, USA.
⁷ Child Health and Human Development Program, McGill University Health Centre Research Institute, Montréal, QC H4A 3J1, Canada; Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, QC H3A 0G4, Canada.
⁸ Department of Molecular Medicine, Faculty of Medicine, Neuroscience Laboratory, CHU de Québec Research Center, Laval University, Quebec City, QC G1V 4G2, Canada.
⁹ Neurology Division, Department of Pediatrics, University of California, San Francisco, Fresno, CA 93701, USA.
¹⁰ Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹¹ Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, 12311 Cairo, Egypt.
¹² Department of Pediatric Neurology, Institute of Child Health, Children Hospital Lahore, 54000 Lahore, Pakistan.
¹³ Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam 1105, the Netherlands.
¹⁴ Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Amsterdam Gastroenterology and Endocrinology Metabolism, Amsterdam 1105, the Netherlands; Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam 1105, the Netherlands; Core Facility Metabolomics, Amsterdam UMC, Amsterdam 1105, the Netherlands.
¹⁵ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada; Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.
¹⁶ Genetic Medicine Division, Department of Pediatrics, University of California, San Francisco, Fresno, CA 93701, USA; Child Health and Human Development Program, McGill University Health Centre Research Institute, Montréal, QC H4A 3J1, Canada; Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Center, Montreal, QC H4A 3J1, Canada.
¹⁷ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada. Electronic address: kboycott@cheo.on.ca.

Abstract

ABHD16A (abhydrolase domain-containing protein 16A, phospholipase) encodes the major phosphatidylserine (PS) lipase in the brain. PS lipase synthesizes lysophosphatidylserine, an important signaling lipid that functions in the mammalian central nervous system. ABHD16A has not yet been associated with a human disease. In this report, we present a cohort of 11 affected individuals from six unrelated families with a complicated form of hereditary spastic paraplegia (HSP) who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls. Our findings add ABHD16A to the growing list of lipid genes in which dysregulation can cause complicated forms of HSP and begin to describe the molecular etiology of this condition.

Keywords: ABHD16A; hereditary spastic paraplegia; intellectual disability; lysophosphatidylserine.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Cerebral Palsy / etiology
Cerebral Palsy / metabolism
Cerebral Palsy / pathology*
Child
Child, Preschool
Cohort Studies
Female
Humans
Intellectual Disability / etiology
Intellectual Disability / metabolism
Intellectual Disability / pathology*
Leukoencephalopathies / etiology
Leukoencephalopathies / metabolism
Leukoencephalopathies / pathology*
Male
Monoacylglycerol Lipases / deficiency
Monoacylglycerol Lipases / genetics*
Mutation*
Pedigree
Phenotype
Spastic Paraplegia, Hereditary / etiology
Spastic Paraplegia, Hereditary / metabolism
Spastic Paraplegia, Hereditary / pathology*
Young Adult

Substances

ABHD16A protein, human
Monoacylglycerol Lipases

Abstract

Publication types

MeSH terms

Substances

Grants and funding